Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions

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Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.

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ABSTRACT-The mechanism of the diuretic action of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxan thine), an adenosine A,-receptor antagonist, was investigated by a lithium clearance study and stop-flow method in anesthetized rats. KW-3902 increased urine volume (UV), sodium excretion and renal clearances of sodium (CNa) and lithium (CLi), when UV and CNa increased more than CLi-KW-3902 did not affect the stop-flow pattern, whereas trichlormethiazide inhibited the reabsorption of water and sodium at the distal nephron. These results suggest that the adenosine A1-receptor blockade exhibits diuretic effects via the in hibition of reabsorption of water and sodium mainly at the proximal tubule. The additional small contribu tion of the distal action can not be ruled out. Keywords:KW-3902, Adenosine A,-receptor antagonist, Diuretic effectAlthough the diuretic effects of alkylxanthines have been known for many years (1), it was only recently found that adenosine receptor antagonism is the basis for this effect. Several years ago, it was demonstrated that 8 phenyltheophylline, a non-selective adenosine receptor antagonist, exhibits a diuretic effect (2). KW-3902 (8is a selective and the most potent adenosine A,-receptor antagonist reported to date (3). KW-3902 significantly increases urine volume and sodium excretion with little change in the potassium excretion of saline-loaded rats (4). There fore, it seems that diuretic effects of adenosine antago nists are due to the blockade of adenosine A,-receptors (5). In the previous study, we found that KW-3902 causes significant diuresis and natriuresis with no change in renal plasma flow and creatinine clearance in anesthetized rats (4). These results suggest that the adenosine A,-receptor antagonist causes diuretic effects by inhibiting reabsorp tion of water and sodium at tubular sites rather than by change in the renal hemodynamics. In the present study, the tubular site of the diuretic action of KW-3902 was in vestigated by a lithium clearance study and stop-flow ex periment.Male Wistar rats (weighing 258 305 g, Japan Shizuoka Laboratory animal Center, Inc., Hamamatsu) were used for the present study, and they were kept at 221C with a 12-hr light-dark cycle. Commercial chow and tap water were available ad libitum before the experiment. Prior to the experiment, rats were anesthetized with urethan (1.3 g/kg, s.c.).In the lithium clearance study, polyethylene catheters were cannulated into left carotid artery, right femoral vein and urinary bladder for blood collection, infusion and urine collection, respectively. After the surgery was completed, saline containing 3 mg/ml lithium carbonate (Wako Pure Chemical Industries, Ltd., Osaka) and 5 pg/ml creatinine (Wako Pure Chemical Industries, Ltd.) was infused with a constant flow infusion pump (Pump 22, Harvard Apparatus Inc., South Natick, MA, USA) at a rate of 2 ml/hr/rat. After equilibration for 90 min, vehi cle was administered to all rats, and urine was collected during a 1-hr control period. After the control period, KW-39...